Background

Agents that target B-cell signaling pathways, such as ibrutinib, idelalisib, and venetoclax, provide durable responses while drastically changing the adverse effect profile in the management of chronic lymphocytic leukemia (CLL).^1–4 Ibrutinib is a first-generation Bruton’s tyrosine kinase inhibitor (BTKi) that has been shown to be effective in frontline and relapsed/refractory CLL, including in patients harboring a 17p deletion.^2,5 Ibrutinib irreversibly binds to BTK, which is stimulated by the B-cell receptor and other cytokine receptors. Ibrutinib and other targeted agents have modified the landscape in the management of CLL.

Similar to CLL, the use of small-molecule tyrosine kinase inhibitors (TKIs) for the management of chronic myeloid leukemia (CML) has led to significant improvement in outcomes. These TKIs (eg, imatinib, dasatinib, nilotinib, bosutinib) have transformed CML from a fatal malignancy to a chronic disease with which most patients achieve a normal life expectancy.^6–10 Despite the success of these therapies, some patients will either not tolerate first-line TKI or not achieve response milestones.^11,12 Second- and third-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib, asciminib) have been shown to be efficacious for second and later lines of therapy, allowing patients to remain on oral therapy for long periods of time, even after other TKIs have failed.^13–17 Nonetheless, these agents are affected by prevalent drug–drug interactions.¹⁸

One potential common target for both CLL and CML is inducing apoptosis through BCL-2.^4,19 The BCL-2 family of proteins regulates the mitochondrial apoptotic response. Constitutionally elevated expression of BCL-2 leads to resistance to apoptosis. Venetoclax, a small molecular inhibitor, mimics BH3 and binds to the BCL-2 protein, causing a displacement of proapoptotic proteins, restoring apoptosis, and causing subsequent malignant cell death. Aberrant BCL-2 activity has been implicated in many types of cancer, including CLL, acute myeloid leukemia, and CML.^4,19–27 Venetoclax is now an established therapeutic option in CLL, for use as first-line therapy or in relapsed/refractory disease.^3,4,28–30 This report presents a case of concomitant use of venetoclax and imatinib for the comanagement of concurrent CLL and CML.

Case Report

The patient was a 73-year-old woman with a remote history of stage I breast cancer status post a partial mastectomy and brachytherapy in 2008, gastroesophageal reflux disease, dyslipidemia, and hypertension. She was diagnosed with CLL in 2012 at an outside facility, and initial immunophenotype, cytogenetics, indications for therapy, and staging were not known. She received one cycle of bendamustine + rituximab, which was complicated by severe anemia. She refused further bendamustine + rituximab therapy and was maintained on active surveillance. Her CLL remained quiescent until August 2018, when she was found to have a worsening WBC count of 31,000/mcL along with worsening lymphadenopathy of the neck, chest, abdomen, axilla, and pelvis. PET/CT imaging showed a new prevertebral soft tissue mass in the nasopharynx with a maximal standardized uptake value of 5.8. This mass was not biopsied. Flow cytometry on a bone marrow biopsy was variably positive for CD20 and CD23 (Figures 1 and 2). Fluorescence in situ hybridization (FISH) on bone marrow was positive for trisomy 12 and 14.q32.3, but negative for TP53 and ATM. It was determined that the patient had Rai stage I CLL. She was started on ibrutinib at 420 mg orally once daily, but the dose was reduced to 280 mg once daily shortly after initiation due to the development of skin rashes. After the dose reduction, her skin rashes resolved. Two years into therapy, restaging CT chest scan showed improvement but not resolution of lymphadenopathy, consistent with partial response.

Figure 1.

Peripheral blood smear showing chronic lymphocytic leukemia/small lymphocytic lymphoma, August 2018. (A) Lymphocytes with numerous smudge cells are visible. (B, C) Bone marrow core biopsy shows diffuse infiltration of small lymphocytes with CD20 expression. On high magnification, a diffuse increase in small lymphocytes is seen.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Figure 2.

Bone marrow aspirate flow cytometry using CD45 versus side scatter (August 2018) separates the cells into regions: granulocytes (R4: 9%), monocytes (R3: 1.4%), and lymphocytes (R8: R2 + R5 + R7 = 83%). Within the lymphocyte population, 78% of clonal B cells (R2: green) represent lambda-restricted CD5(+) and CD23(+). Proliferation index showed 5% positivity.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

In October 2020, the patient presented to our lymphoma service for management and was found to have leukocytosis and mediastinal lymphadenopathy but no organomegaly, remaining Rai stage I. At presentation, the patient reported fatigue; otherwise the physical examination was unremarkable. She was found have a resolved hepatitis B infection, and tenofovir was initiated. A subcarinal lymph node biopsy was completed in January 2021 (Figure 3), which was positive for CD45, CD5 (dim), CD11c (dim), CD19, CD20, CD22, CD52, and monotypic surface lambda light chain, consistent with persistent CLL via flow cytometry. Due to worsening lymphadenopathy and flow cytometry results, a decision was made to change therapy to venetoclax with rituximab. Shortly before the initiation of venetoclax in late February 2021, the patient underwent a PET scan, but no PET-avid disease was identified. A FISH panel on peripheral blood was found to be normal.

Figure 3.

Lymph node core needle biopsy from patient in January 2021 after 2 years of therapy using ibrutinib, 280 mg once daily. (A, B) Hematoxylin-eosin staining from subcarinal lymph node biopsy reveals effacement of the lymph node architecture by medium-sized CD20-positive lymphocytes.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

At the initiation of venetoclax in early March 2021, the patient’s WBC count was 66,900/mcL. After completing only week 1 of venetoclax at 20 mg once daily, her WBC count increased to 74,400/mcL, with increases in neutrophils and metamyelocytes (Table 1). Given her peripheral blood FISH and PET scan results and increasing absolute neutrophil count and basophilia during week 2 of venetoclax at 50 mg once daily, a bone marrow biopsy was performed. Results showed hypercellular bone marrow (95%) with CML with 1% blasts, and flow cytometry showed residual low-grade B-cell lymphoma (<5%) (Figure 4). A karyogram of this sample showed 46,XX,t(9;22)(q34;q11.2), and FISH identified 182/200 nuclei positive for BCR::ABL1 fusion (Figure 5). The final diagnosis was confirmed as chronic phase CML, in addition to the already known CLL. When the ramp-up phase was completed, ibrutinib was stopped, imatinib was started at a dose of 400 mg daily, and venetoclax was continued at a maintenance dose of 200 mg daily, given that imatinib is an inhibitor of cytochrome P450 3A4 (CYP3A4).

Table 1.

Blood Counts

Figure 4.

Peripheral blood smear, bone marrow biopsy, and aspirate particles in March 2021. (A, B) Leukocytosis with granulocytic left shift, nontoxic neutrophilia, and basophilia (inset, A) and rare blast (inset, B) are the classic features of BCR::ABL1–positive chronic phase CML. (C) Megakaryocytes in CML are small and hypolobated in contrast to other classic myeloproliferative neoplasms. (D) Low- and high-power magnification of hypercellular bone marrow core biopsy with increased myeloid-to-erythroid ratio. MPO staining highlights left-shifted myeloid element (inset, D).

Abbreviations: CML, chronic myeloid leukemia; MPO, myeloperoxidase.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Figure 5.

Karyogram and FISH studies from bone marrow sample, March 2021. Karyogram highlights the classic chromosome 22 (Philadelphia) in CML. (A) The reciprocal translocation involves 9q34 and 22q11.2 juxtaposing the ABL1 and BCR genes at the molecular examination. (B) FISH using dual-fusion probe shows the presence of a BCR::ABL1 gene fusion (arrows).

Abbreviations: CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization.

Citation: Journal of the National Comprehensive Cancer Network 21, 2; 10.6004/jnccn.2022.7069

Rituximab was added to venetoclax therapy, with the last rituximab dose being given in November 2021. She is currently continuing imatinib and venetoclax therapy for comanagement of her CML and CLL. She has tolerated both imatinib and venetoclax very well with only mild leukopenia, anemia, neutropenia, and nausea managed with ondansetron. At the time of writing, her response to venetoclax therapy is unknown because restaging imaging has not occurred. Regarding her CML, she has experienced a major molecular remission (Table 2).

Table 2.

BCR::ABL Transcript-Level Trends and Response to Imatinib Therapy

Discussion

Several aspects of this case report are noteworthy. Venetoclax dosing with imatinib requires consideration. After daily administration under fed conditions, the venetoclax maximum concentration is reached within 5 to 8 hours and is oxidized by cytochrome P450 3A to its inactive metabolite.³¹ After single and multiple doses, strong inhibitors of CYP3A4 have resulted in a 2.3- to 2.4-fold increase in maximum concentration and a 6.9- to 8.1-fold increase in the area under the curve.^31–33 Imatinib is a known substrate and a moderate inhibitor of CYP3A4 and cytochrome P450 3A5.^34,35 For this reason, the venetoclax dose was chosen to be 200 mg once daily for this patient. To date, she has tolerated concomitant therapy well.

Synchronous occurrence of CLL and CML is rare. Although secondary malignancies with CLL are common, most are found to be skin, prostate, and breast cancers.³⁶ In addition, malignancy post-BTK therapy can also be problematic in CLL.^37,38 Secondary CML has been reported, but it does not have additional cytogenetic abnormalities typically found with other secondary cancers, such as acute myeloid lekemia.³⁹ A handful of concurrent CML and CLL cases have been reported in the literature spanning 30 years that have successfully been comanaged.^40–44 Targeted therapies have also been used successfully in a few cases, strengthening the argument that combination therapies can be safely and effectively administered in these rare patients.^45,46

The most compelling component of this case report is that it highlights the safety and efficacy of concomitant venetoclax and imatinib. Both are well-established therapies in their respective diseases; however, concurrent CML and CLL are exceptionally rare. In preclinical models, venetoclax and navitoclax have activity in CML.¹⁹ Venetoclax activity is related directly to the expression of BCL-2 in CML but is modest at best as a single agent in several CML cell lines. When combined with imatinib, venetoclax enhanced imatinib-induced apoptosis in cell lines higher in BCL-2 expression. The present case report also corroborates a reported case series demonstrating that the concomitant use of venetoclax and TKIs is safe and effective.⁴⁷ In addition, venetoclax has been shown to target leukemia stem cells,^48,49 which are believed to be responsible for the initiation and perpetuation of leukemias and are known to be resistant to traditional chemotherapy and TKIs. And finally, adding TKIs to venetoclax has been shown to overcome venetoclax resistance through inducing Lck/Yes-related novel tyrosine kinase–mediated proapoptotic BCL-2–like protein 11 expression and inhibiting the upregulation of antiapoptotic MCL-1.⁵⁰

Given all of this information, a compelling argument can be made for combination therapy using venetoclax plus TKIs as a novel and attractive approach for CML to obtain treatment-free remission and potentially a cure. However further studies, particularly prospective in nature, are needed to evaluate this combination from a treatment perspective and for treatment-free remission attempts.

Conclusions

This case report represents the second report on the use of venetoclax plus TKIs for CML and is the first report on the use of venetoclax plus TKIs for concomitant CLL and CML. Concomitant oral BCL-2 and TKI therapy was shown to be safe and efficacious, but given the unique pharmacokinetic and pharmacodynamic profiles of these drugs, careful monitoring and management of adverse events with this combination is warranted. Future studies of this novel treatment combination are needed.